New biaryl amide derivatives

Abstract

The invention provides novel compounds having the general formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and A are as described herein, compositions including the compounds and methods of using the compounds.

1 . A compound according to formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, cycloalkoxyalkyl, haloalkyl, haloalkoxyalkyl, halocycloalkyl, halocycloalkylalkyl, halocycloalkoxyalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, wherein substituted aryl and substituted heteroaryl are substituted with one to three substituents independently selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, alkylcycloalkylalkyl, halocycloalkyl, halocycloalkylalkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, hydroxyalkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, hydroxyhaloalkyl, amino and substituted amino, wherein substituted amino is substituted with one to two substituents independently selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl and alkoxyalkyl; 
         R 2  is selected from the group consisting of hydrogen, alkyl and cycloalkyl; 
         R 3  is selected from the group consisting of hydrogen, alkyl and cycloalkyl; 
         R 4  is selected from the group consisting of hydrogen, alkyl and cycloalkyl; 
         R 5  is selected from the group consisting of hydrogen, alkyl and cycloalkyl; 
         or R 4  and R 5  together form a cycloalkyl with the carbon they are attached to; 
         R 6  is selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, halogen and cyano; 
         R 7  is selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, halogen and cyano; 
         R 8  is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, halocycloalkyl, halocycloalkylalkyl, halocycloalkoxy, halocycloalkoxyalkyl, alkoxycarbonyl, cycloalkoxycarbonyl, haloalkoxycarbonyl, halocycloalkoxycarbonyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, wherein substituted aryl and substituted heteroaryl are substituted with one to three substituents independently selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, alkylcycloalkylalkyl, halocycloalkyl, halocycloalkylalkyl, halogen, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, amino and substituted amino, wherein substituted amino is substituted with one to two substituents independently selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl and alkoxyalkyl; 
         R 9  is selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, halogen and cyano; 
         R 10  is selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, halogen and cyano; 
         R 11  is selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, halogen and cyano; 
         R 12  is selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, halogen and cyano; 
         R 13  is selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, halogen and cyano; and 
         A is CR 13  or N; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A compound according to  claim 1 , wherein R 1  is selected from the group consisting of alkoxyalkyl, cycloalkoxyalkyl, haloalkyl, haloalkoxyalkyl, halocycloalkyl, halocycloalkylalkyl, halocycloalkoxyalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, wherein substituted aryl and substituted heteroaryl are substituted with one to three substituents independently selected from the group consisting of alkyl, cycloalkyl, halogen, haloalkyl, alkoxy, alkoxyalkyl, amino and substituted amino, wherein substituted amino is substituted with one to two substituents independently selected from alkyl and cycloalkyl. 
     
     
         3 . A compound according to  claim 1 , wherein R 1  is selected from the group consisting of alkoxyalkyl, haloalkyl, substituted phenyl, heteroaryl and substituted heteroaryl, wherein substituted phenyl and substituted heteroaryl are substituted with one to three substituents independently selected from the group consisting of alkyl, halogen, haloalkyl, alkoxy, and amino. 
     
     
         4 . A compound according to  claim 1 , wherein R 1  is selected from the group consisting of alkoxyalkyl, haloalkyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridizanyl, and pyrimidinyl,
 or is selected from the group consisting of phenyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridizanyl, and pyrimidinyl substituted with one to three substituents independently selected from the group consisting of alkyl, halogen, haloalkyl, alkoxy, and amino.   
     
     
         5 . A compound according to  claim 1 , wherein R 1  is selected from the group consisting of alkoxyalkyl, haloalkyl, isoxazolyl, pyridizanyl, pyrimidinyl, halo-haloalkylphenyl, alkylimidazolyl, alkylisoxazolyl, alkoxyisoxazolyl, alkyloxadiazolyl, alkylthiadiazolyl, aminopyridinyl and alkoxypyrimidinyl. 
     
     
         6 . A compound according to  claim 1 , wherein R 8  is selected from the group consisting of haloalkoxy, alkoxycarbonyl, cycloalkoxycarbonyl, haloalkoxycarbonyl, heteroaryl and substituted heteroaryl, wherein substituted heteroaryl is substituted with one to three alkyl. 
     
     
         7 . A compound according to  claim 1 , wherein R 8  is selected from the group consisting of haloalkoxy, alkoxycarbonyl and substituted heteroaryl, wherein substituted heteroaryl is substituted with one to three alkyl. 
     
     
         8 . A compound according to  claim 1 , wherein R 8  is selected from the group consisting of haloalkoxy, alkoxycarbonyl, alkyltetrazolyl and alkyloxadiazolyl. 
     
     
         9 . A compound according to  claim 1 , wherein one of R 4  and R 5  is hydrogen and the other is alkyl. 
     
     
         10 . A compound according to  claim 1 , wherein R 4  and R 5  together form a cycloalkyl with the carbon they are attached to. 
     
     
         11 . A compound according to  claim 1 , wherein A is CR 13 . 
     
     
         12 . A compound according to  claim 1 , wherein A is N. 
     
     
         13 . A compound according to  claim 1 , selected from the group consisting of:
 3-(3-Fluoro-5-trifluoromethyl-benzoylamino)-oxetane-3-carboxylic acid ((R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethyl)-amide;   3-(2,2,2-Trifluoro-acetylamino)-oxetane-3-carboxylic acid ((R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethyl)-amide;   Isoxazole-5-carboxylic acid [3-((R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   3-Methyl-isoxazole-5-carboxylic acid [3-((R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   Pyrimidine-5-carboxylic acid [3-((R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   3-Chloro-3′-fluoro-4′-((R)-1-{[3-(2,2,2-trifluoro-acetylamino)-oxetane-3-carbonyl]-amino}-ethyl)-biphenyl-2-carboxylic acid methyl ester;   3-Chloro-3′-fluoro-4′-[(R)-1-({3-[(pyrimidine-5-carbonyl)-amino]-oxetane-3-carbonyl}-amino)-ethyl]-biphenyl-2-carboxylic acid methyl ester;   3-Chloro-3′-fluoro-4′-((R)-1-{[3-(3,3,3-trifluoro-propionylamino)-oxetane-3-carbonyl]-amino}-ethyl)-biphenyl-2-carboxylic acid methyl ester;   3-Methyl-isoxazole-5-carboxylic acid [3-((R)-1-{5-[3,5-dichloro-2-(2,2-difluoro-ethoxy)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   Isoxazole-5-carboxylic acid [3-((R)-1-{5-[3,5-dichloro-2-(2,2-difluoro-ethoxy)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   and pharmaceutically acceptable salts thereof.   
     
     
         14 . A compound according to  claim 1 , selected from the group consisting of:
 Pyrimidine-5-carboxylic acid [3-((R)-1-{5-[3,5-dichloro-2-(2,2-difluoro-ethoxy)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   3-Chloro-3′-fluoro-4′-[(R)-1-({3-[(isoxazole-5-carbonyl)-amino]-oxetane-3-carbonyl}-amino)-ethyl]-biphenyl-2-carboxylic acid methyl ester;   3-Chloro-3′-fluoro-4′-[(R)-1-({3-[(3-methyl-isoxazole-5-carbonyl)-amino]-oxetane-3-carbonyl}-amino)-ethyl]-biphenyl-2-carboxylic acid methyl ester;   3-Methoxy-isoxazole-5-carboxylic acid [3-((R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   2-Methoxy-pyrimidine-5-carboxylic acid [3-((R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid [3-((R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   3-(2-Methoxy-acetylamino)-oxetane-3-carboxylic acid ((R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethyl)-amide;   3-Methoxy-isoxazole-5-carboxylic acid [3-((R)-1-{5-[3,5-dichloro-2-(2,2-difluoro-ethoxy)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   5-Methyl-[1,3,4]oxadiazole-2-carboxylic acid [3-((R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   3-Methyl-isoxazole-5-carboxylic acid [3-((R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   and pharmaceutically acceptable salts thereof.   
     
     
         15 . A compound according to  claim 1 , selected from the group consisting of:
 3-(2,2,2-Trifluoro-acetylamino)-oxetane-3-carboxylic acid ((R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethyl)-amide;   3-(2,2,2-Trifluoro-acetylamino)-oxetane-3-carboxylic acid {(R)-1-[5′-chloro-3,3′-difluoro-2′-(2-methyl-2H-tetrazol-5-yl)-biphenyl-4-yl]-ethyl}-amide;   3-Methyl-isoxazole-5-carboxylic acid (3-{(R)-1-[5′-chloro-3,3′-difluoro-2′-(2-methyl-2H-tetrazol-5-yl)-biphenyl-4-yl]-ethylcarbamoyl}-oxetan-3-yl)-amide;   3-Methyl-isoxazole-5-carboxylic acid (3-{(R)-1-[5′-chloro-3,3′-difluoro-2′-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-yl]-ethylcarbamoyl}-oxetan-3-yl)-amide;   Pyridazine-4-carboxylic acid [3-((R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   1-Methyl-1H-imidazole-2-carboxylic acid [3-((R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   1-Methyl-1H-imidazole-4-carboxylic acid [3-((R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   5-Amino-N-[3-((R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-nicotinamide;   Pyridazine-3-carboxylic acid [3-((R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   N-[3-((R)-1-{5-[5-Chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-nicotinamide;   and pharmaceutically acceptable salts thereof.   
     
     
         16 . A compound according to  claim 1 , selected from the group consisting of:
 2-Methoxy-pyrimidine-5-carboxylic acid (3-{(R)-1-[5′-chloro-3,3′-difluoro-2′-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-yl]-ethylcarbamoyl}-oxetan-3-yl)-amide;   Isoxazole-5-carboxylic acid (3-{(R)-1-[3′,5′-dichloro-2′-(2,2-difluoro-ethoxy)-3-fluoro-biphenyl-4-yl]-ethylcarbamoyl}-oxetan-3-yl)-amide;   3-(2,2,2-Trifluoro-acetylamino)-oxetane-3-carboxylic acid {(R)-1-[3′,5′-dichloro-2′-(2,2-difluoro-ethoxy)-3-fluoro-biphenyl-4-yl]-ethyl}-amide;   3-Methoxy-isoxazole-5-carboxylic acid [3-((R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   2-Methoxy-pyrimidine-5-carboxylic acid (3-{(R)-1-[3′,5′-dichloro-2′-(2,2-difluoro-ethoxy)-3-fluoro-biphenyl-4-yl]-ethylcarbamoyl}-oxetan-3-yl)-amide;   2-Methoxy-pyrimidine-5-carboxylic acid [3-((R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   3-Methoxy-isoxazole-5-carboxylic acid (3-{(R)-1-[3′,5′-dichloro-2′-(2,2-difluoro-ethoxy)-3-fluoro-biphenyl-4-yl]-ethylcarbamoyl}-oxetan-3-yl)-amide;   5-Methyl-[1,3,4]oxadiazole-2-carboxylic acid (3-{(R)-1-[3′,5′-dichloro-2′-(2,2-difluoro-ethoxy)-3-fluoro-biphenyl-4-yl]-ethylcarbamoyl}-oxetan-3-yl)-amide;   5-Methyl-[1,3,4]oxadiazole-2-carboxylic acid [3-((R)-1-{5-[3,5-dichloro-2-(2,2-difluoro-ethoxy)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   2-Methoxy-pyrimidine-5-carboxylic acid [3-((R)-1-{5-[3,5-dichloro-2-(2,2-difluoro-ethoxy)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   and pharmaceutically acceptable salts thereof.   
     
     
         17 . A compound according to  claim 1 , selected from the group consisting of:
 4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid [3-((R)-1-{5-[3,5-dichloro-2-(2,2-difluoro-ethoxy)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   3-(2-Methoxy-acetylamino)-oxetane-3-carboxylic acid ((R)-1-{5-[3,5-dichloro-2-(2,2-difluoro-ethoxy)-phenyl]-3-fluoro-pyridin-2-yl}-ethyl)-amide;   3-Methoxy-isoxazole-5-carboxylic acid (3-(R)-1-[5′-chloro-3,3′-difluoro-2′-(2-methyl-2H-tetrazol-5-yl)-biphenyl-4-yl]-ethylcarbamoyl-oxetan-3-yl)-amide;   2-Methoxy-pyrimidine-5-carboxylic acid (3-{(R)-1-[5′-chloro-3,3′-difluoro-2′-(2-methyl-2H-tetrazol-5-yl)-biphenyl-4-yl]-ethylcarbamoyl}-oxetan-3-yl)-amide;   and pharmaceutically acceptable salts thereof.   
     
     
         18 . A compound according to  claim 1 , selected from the group consisting of:
 3-Methyl-isoxazole-5-carboxylic acid [3-((R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   3-Methoxy-isoxazole-5-carboxylic acid [3-((R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   2-Methoxy-pyrimidine-5-carboxylic acid [3-((R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   5-Methyl-[1,3,4]oxadiazole-2-carboxylic acid [3-((R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   3-Methyl-isoxazole-5-carboxylic acid [3-((R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   Pyridazine-3-carboxylic acid [3-((R)-1-{5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   2-Methoxy-pyrimidine-5-carboxylic acid [3-((R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-3-fluoro-pyridin-2-yl}-ethylcarbamoyl)-oxetan-3-yl]-amide;   and pharmaceutically acceptable salts thereof.   
     
     
         19 . A pharmaceutical composition comprising a compound according to  claim 1  and a therapeutically inert carrier.